Inter-relationships between the metabolic syndrome, insulin resistance and salt-sensitive hypertension
The metabolic syndrome, namely the clustering of disturbances in glucose metabolism, dyslipidaemia, central obesity and essential hypertension, is a powerful predictor of cardiovascular disease [1–3]. Although there are several different definitions of the metabolic syndrome, hypertension is included in all [4–7]. The cause of the metabolic syndrome is largely unknown, although insulin resistance has been suggested to be a common link between its individual components . The pathophysiological relationship between hypertension and the other more classically metabolic traits of the syndrome seems particularly intriguing, and new knowledge in this field may be of great importance for the understanding and treatment of essential hypertension.
Reduced salt intake lowers blood pressure, although the magnitude of the reduction in the general population is widely debated [9–11]. It is well established that salt sensitivity, namely the individual blood pressure-lowering effect of reduced salt intake, varies between individuals. Hypertensive patients are more salt sensitive than normotensive individuals , and normotensive individuals with heredity for hypertension are more salt sensitive than those without such a family history [13,14], suggesting that salt sensitivity is part of the inherited predisposition of essential hypertension. Interestingly, insulin resistance is also associated with a family history of hypertension in normotensive individuals , raising the question of whether salt sensitivity and insulin resistance are related hypertension-associated traits. Both normotensive and hypertensive salt-sensitive individuals have been shown to be hyperinsulinaemic [16,17], insulin resistant [18–20], or both when compared with salt-resistant individuals; however, the finding has not been universal . Considering the central role of insulin resistance in the metabolic syndrome, it is possible that the syndrome is linked to salt-sensitive hypertension. In the present issue of the journal, Uzu and co-workers  report associations between the presence of the metabolic syndrome and salt-sensitive hypertension. Furthermore, central obesity, the core criterion for the metabolic syndrome according to the definition proposed by the International Diabetes Federation , was independently associated with salt sensitivity .
Potential molecular mechanisms linking the metabolic syndrome with hypertension and salt sensitivity
Blood pressure and hypertension are highly heritable traits [23,24], but the normal distribution of blood pressure at the population level suggests a polygenic and multifactorial aetiology in the majority of hypertensive patients. Interestingly, a number of salt-sensitive monogenic forms of hypertension have been explained at the molecular level. The mutations causing these disorders directly or indirectly lead to the over-expression of either the amiloride-sensitive epithelial sodium channel (ENaC) or the thiazide-sensitive NaCl co-transporter expressed in the distal nephron [25–30]. One of the first monogenic forms of hypertension to be explained at the molecular genetic level, Liddle's syndrome, is caused by mutations in the C-terminus of ENaC . Normally, the protein neuronal precursor cell expressed developmentally downregulated 4-like (NEDD4L) removes ENaC from the tubular apical cell surface in the renal collecting ducts by binding to the C-terminus of ENaC [31,32], thereby keeping ENaC expression at a controlled level. The ENaC mutations in Liddle's syndrome delete or alter the ENaC C-terminus, leading to inhibiton of the NEDD4L–ENaC interaction. This results in over-expression of ENaC, renal hyper-reabsorption of sodium and salt-sensitive hypertension.
Although Liddle's syndrome patients do not typically display a metabolic syndrome phenotype, and hypertension-causing ENaC mutations are rare , these findings contributed to the discovery of a new signalling pathway that could be a central link between salt-sensitive hypertension and the metabolic syndrome. The ENaC channel remover NEDD4L is regulated by the serum and glucocorticoid regulated kinase 1 (SGK1), which in turn is regulated by the renin–angiotensin–aldosterone system and by insulin . Aldosterone bound to the mineralocorticoid receptor binds to the SGK1 promoter and drives up SGK1 expression, whereas insulin, via its effects on phosphatidylinositol-3-kinase, activates SGK1 through phosphorylation. The activation of SGK1 by insulin as well as increased SGK1 expression by aldosterone thus inhibits NEDD4L to remove ENaC from the renal tubular cells, which in turn would be expected to cause increased renal sodium reabsorption and salt sensitivity.
Peripheral insulin resistance and its close companion of central obesity lead to compensatory hyperinsulinaemia. Importantly, although the muscle is resistant to insulin-mediated glucose uptake in insulin-resistant states, such as in hypertension and in normotensive individuals with a positive family history of hypertension, the sodium-retaining effect of insulin at the level of the kidney is maintained at normal [35,36]. The compensatory hyperinsulinaemia seen in the metabolic syndrome could thus be speculated to cause salt-sensitive hypertension through increased load on the SGK1–NEDD4L–ENaC interaction. Interestingly, common genetic variance of SGK1 leads to higher blood pressure at the population level . Although the fasting plasma concentration of insulin is positively correlated with blood pressure regardless of genetic variants of SGK1, individuals carrying the blood pressure-elevating variants of the SGK1 gene had a significantly stronger correlation between the fasting plasma concentration of insulin and diastolic blood pressure than did those who did not carry these genetic variants . Again, this suggests that the interaction between insulin and SGK1 may elevate blood pressure and the risk of hypertension through increased EnaC-mediated renal sodium reabsorption.
Implications for treatment of hypertension in the metabolic syndrome
The findings by Uzu et al. , suggesting an association between salt-sensitive hypertension and the metabolic syndrome, together with recent studies highlighting the role of the insulin–SGK1–NEDD4L–ENaC system , may have relevance for the treatment of hypertension in the metabolic syndrome. Interventions specifically targeted at the insulin–SGK1–NEDD4L–ENaC system would seem attractive. This may include interventions lowering circulating insulin concentrations as can be achieved by improving peripheral insulin sensitivity. The blood pressure-lowering effect of physical exercise and insulin-sensitizing drugs, such as thiazolidinediones , could thus be mediated through decreased load on the insulin–SGK1–NEDD4L–ENaC system. Furthermore, dietary salt restriction should be included as first-line life-style therapy for the metabolic syndrome together with physical exercise. The findings also encourage new studies on the antihypertensive and cardioprotective effects of amiloride as well as on the development of specific SGK1 inhibitors and NEDD4L enhancers in the treatment of hypertension in the metabolic syndrome.
The proposed relationship between the metabolic syndrome and salt-sensitive hypertension needs to be confirmed in other studies. Furthermore, although likely to be the case, it is still not entirely clear whether the metabolic syndrome adds predictive value for cardiovascular disease independently of classical cardiovascular risk factors, and whether the different definitions of the syndrome predict cardiovascular disease equally well. The exact role of the newly discovered insulin–SGK1–NEDD4L–ENaC system in the pathogenesis of salt-sensitive hypertension in the metabolic syndrome and its clinical relevance remains to be shown. However, the potential links between the metabolic syndrome, salt-sensitive hypertension and the insulin–SGK1–NEDD4L–ENaC system is definitely a promising and refreshing research field for the next few years.
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